Methods of controlling liver fluke infections

ABSTRACT

Salicylanilides having an aromatic ring linked to the aniline moiety by one or more non-metallic atoms. Processes for the preparation of novel salicylanilides. Compositions useful in the treatment of parasitic diseases containing a substituted salicylanilide as an active ingredient.

United States Patent Patchett et al.

[4 1 Oct. 21, 1975 METHODS OF CONTROLLING LIVER FLUKE INFECTIONSInventors: Arthur A. Patchett, Cranford;

I-Ielmut H. Mrozik, Matawan; Dale R. Hoff, Basking Ridge, all of NJ.

Assignee: Merck & Co., Inc., Rahway, NJ.

Filed: Aug. 24, 1973 App]. No.: 391,199

Related U.S. Application Data Division of Ser. No. 177,906, Sept. 2,1971, abandoned, which is a division of Ser. No. 19,487, March 13, 1970,Pat. No. 3,798,258, which is a continuation-in-part of Ser. No. 634,442,April 28,

i i 1967, abandoned, which is a continuation-in-part of Ser. No.573,474, Aug. 10, 1966, abandoned, which is a continuation-in-part ofSer. No. 555,694, June 7, 1966, abandoned.

' U.S. Cl. 424/230 Int. Cl. A61K 31/60 Field of Search 424/230; 260/479R, 559

l/l966 Greece 260/559 Primary Examiner-Albert T. Meyers AssistantExaminerLeonard Schenkman Attorney, Agent, or Firm-J. Jerome Behan;David L. Rose [57] ABSTRACT Salicylanilides having an aromatic ringlinked to the aniline moiety by one or more non-metallic atoms.Processes for the preparation of novel salicylanilides. Compositionsuseful in the treatment of parasitic diseases containing a substitutedsalicylanilide as an active ingredient.

4 Claims, No Drawings DESCRIPTION OF THE PREFERRED EMBODIMENTS Thisinvention relates to a novel class of chemical compounds described assalicylanilides. More specifically, it relates to novel salicylanilideswhich carry an aromatic ring on the anilide moiety linked theretothrough one or more non-metallic atoms. Furthermore, it relates to novelsalicylanilides useful in the treatment of parasitic diseases, tomethods of preparing and using them, and to compositions containingthem.

The novel salicylanilides of the present invention are structurallydepicted as follows:

Z Z Y 6 :I; I 4 Z4 Y wherein A is hydrogen or loweralkanoyl containing24 carbon atoms, such as acetyl, propionyl or butyryl; Y is hydrogen,halogen, such as bromine, chlorine,

iodine or fluorine, cyano, nitro, loweralkyl containing l-4 carbons suchas methyl, ethyl and butyl;

Y, is hydrogen or trifluoromethyl;

Y is hydrogen, halogen, or nitro;

Y is hydrogen, halogen, hydroxy, loweralkoxy containing l-4 carbons,such as methoxy, ethoxy, and butoxy, or loweralkanoyloxy containing 2-4carbons, such as acetoxy, propionyloxy, or butyryloxy;

X is hydrogen, hydroxy, halogen, nitro, trifluoromethyl, or loweralkoxycontaining l-4 carbons, such as methoxy, ethoxy, or butoxy;

X is hydrogen, halogen, trifluoromethyl, nitro, amino, or loweralkoxycontaining l4 carbons, such as methoxy, ethoxy, or butoxy;

X is hydrogen or halogen;

X is hydrogen or halogen;

Q is oxygen or sulfur;

Z is hydrogen, halogen, or loweralkyl containing l-4 carbons;

Z is hydrogen, halogen, trifluoromethyl, loweralkyl containing l-4carbons, such as methyl, ethyl, or butyl, or cyano;

Z is hydrogen, halogen, cyano, nitro, trifluoromethyl, loweralkylcontaining l-4 carbons, such as methyl, ethyl, or butyl, or loweralkoxycontaining 1-4 carbons;

Z is hydrogen, halogen, or trifluoromethyl; and

Z is hydrogen or halogen; provided that Ring C is linked to Ring B ateither the 3 'or 4 position of Ring B, and that no more than threesubstituents other than hydrogen are present on any one of the aromaticrings at any one time, i.e., at least one of X, Y and Z is hydrogen. Theterm halogen is intended to include bromine, chlorine, iodine andfluorine. Where Ring C is attached to Ring B at the 3 position, thesubstituent X is in the 4' position.

Also within the scope of the present invention are the pharmaceuticallyacceptable replacement or amine addition salts of Compound I, such asmetal salts, exemplified by sodium, potassium, calcium, copper, iron,and the like, and amines salts as the pyridine, piperazine, methylamine,ethanolamine salts, and the like. It is also contemplated that the novelsalicylanilides of this invention can be employed in combination withother known, non-antagonistic anthelmintic agents such as thiabendazole,tetramisol, organo phosphorous compounds, piperazine, phenothiazine,certain antimony compounds, or with certain antibacterial agents such asthe sulfonamides, certain penicillin preparations, certain antibiotics,and the like. The type of combination to be employed would depend uponthe type and degree of infection to be combatted and the mode ofadministration.

As can be seen from the foregoing structural formula, the compounds ofthe present invention are tricyclic in which each ring is variouslysubstituted. Those compounds wherein Q is either oxygen or sulfur,namely the phenoxysalicylanilides and phenylthiosalicylanilides, and X,Y and Z are halogen, hydroxy, nitro or trifluoromethyl represent apreferred subclass of the compounds of the present invention. Alsowithin the scope of the present invention are the sulfinyl and sulfonylsalicylanilides which can be prepared from those compounds where Q issulfur by techniques known in the art. The point of attachment betweenthe anilide ring moiety B and the nuclear ring moiety can be at a carboneither para or meta to the nitrogen of the anilide, i.e., at the 3 or 4position of Ring B. The para position is the preferred point ofattachment.

Typical of the compounds within the scope of the present inventionwherein the total substituents other than hydrogen in Rings B and C is Oor 1 are:

3,5-dibromo-4'-phenoxysalicylanilide3,5-dichloro-4'-phenoxysalicylanilide 3,5-diiodo-4-phenoxysalicylanilide3,5-dibromo-4'-(m-trifluoromethylphenoxy)- salicylanilide3,5-dibromo-4.'-(p-methoxyphenoxy)-salicylanilide3,5-dichloro-4'-(m-ethoxyphenoxy)-salicylanilide3,5-dichloro4'-(m-ethoxyphenoxy)-salicylanilide3,5-dibromo-4'-(p-nitrophenoxy)-salicylanilide3,5-diiodo-4'-(o-nitrophenoxy)-salicylanilide3,5-dibromo-4-(p-cyanophenoxy)-salicylanilide3,5-dibromo-4'-(pbromophenoxy)-salicylanilide3,5-dichloro-4'-(p-bromophenoxy)-salicylanilide3,5-dibromo-4'-(p-chlorophenoxy)-salicylanilide3,5-dichloro-4'-(p-chlorophenoxy)-salicyanilide3,5-diiodo-4'-(o-chlorophenoxy)-salicylanilide3,5-dibromo-4'-(o-bromophenoxy)-salicylanilide 3 ,5-dibromo-3 -chloro4'-phenoxysalicylanilide 3 ,5-dichloro-4 -chloro-3'-phenoxysalicylanilide 3 ,5=dibromo-4 p-bromophenylsulfonylsalicylanilide 3 ,5-dibromo-3 '-chloro-4 '-(p-chlorophenylsulfonylsalicylanilide 3 ,5-dibromo-3 '-chloro-4 '-(p-chlorophenylsulfinylsalicylanilide 3 ,5-dibromo-3 -trifluoromethyl-4p-nitrophenylsulfonyl)-salicylanilide3,5-dibromo-4'-(p-nitrophenylsulfonyl)- salicylanilide3,5-dibromo-6-hydroxy-4'-(p-fluorophenylthio)- salicylanilide3,5-dibromo-4-(p-fluorophenylthio)-salicylanilide 3 ,5-dibromo-4m-trifluoromethylphenylthio salicylanilide and the like.

The preferred compounds among the foregoing are:

3 ,5-dibromo-3 '-chloro-4 '-(p-chlorophenoxy salicylanilide 3,5-dibromo-3 -chloro-4 -(o,p-dichlorophenoxy salicylanilide3-nitro-5-bromo-3 '-chloro-4-(p-chlorophenoxy)- salicylanilide 3 ,5-dibromo-3 -bromo-4 '-(p-bromophenoxy salicylanilide 3,5-dibromo-6-hydroxy-4 '-chloro-3 -(p-chlorophenoxy )-salicylanilide 63,5-dibromo-2'-chloro-4'-(p-chlorophenoxy)- salicylanilide3,5-dibromo-6-hydroxy-4'-(p-fluorophenylthio)- salicylanilide3,5-dibromo-4'-(m,p-dichlorophenoxy salicylanilide 3,5-dibromo-4'-rn-trifluoromethylphenoxy)- salicylanilide 3 ,5-dibromo-2 ;5 -dichloro-4 p-chlorophenoxy salicylanilide3,5-dibromo-4'-(p-fluorophenylthio)-salicylanilide,

and 3,5-dibromo-4'-(m-trifluoromethylphenylthio)- salicylanilide;

The compounds of the present invention are prepared by condensing anappropriately substituted salicylic acid compound containing anactivating group in the carboxylic acid sidechain (Compound II) with ananiline compound substituted at the 3 or 4 position with a secondaromatic ring, said rings being joined together by an oxygen or sulfuratom, with optional substitution on the remaining carbon atoms of eachof the aromatic rings, hereinafter referred to as a substituted anilinecompound (Compound III) as shown by the following flow diagram:

(IVa) where D is an activating group such as chlorine orbromine: Aequals hydrogen or loweralkanoyli and X -X Y Y 2 -2 are Q are as definedabove, provided that Ring B is linked to Ring C at either the 3 or '4position ofRing B. 1

The activated salicylic acid compound-canalso be reacted with anapporpiately substituted aniline compound in the presence of a Lewisacid such as boron trifluoride or alkali such as sodium hydroxide orjust-with heating, depending upon the type of activating' 'g'roup on thesalicylic acid'compound.

Where the activating group is halogen, one can also first react the acidhalid with ammonia to form the amide, and then react the amide with asubstituted aniline in the presence of a suitable alkali. Byappropriately substituted is meant that those'substituentsY, X and Z,which arefldesiredin the final product-(Compound I), are present in thereagent Compounds II and III.

Where the acid halide is reacted directly with the substituted aniline,the reaction is carried out in-the presence of a solvent via insituformed acid halide. I

This may be achieved by comining the free acid with chloride,tribromide, pentachloride, pentabromide, ox-

alylchloride, silicon tetrachloride, and the like. The temperature ofthe reaction is not critical, suitable results being obtained attemperatures ranging from room temperature to the reflux temperature ofthe reaction mass. It is preferred, however, to conduct the reaction atelevated temperatures (since room temperature reactions may beuneconomical and time consuming) and most preferably at the refluxtemperature of the system. As suitable solvents there may be employedaromatic compounds such as benzene, toluene, xylene; halogenatedaromatic compounds such as chlorobenzene and dichlorobenze; halogenatedhydrocarbons such as chloroform, tetrachloroethane; carbontetrachloride, methylene, chloride; ethers such as dioxane,diethylether, dimethoxyethane; and the like. Halogenated aromaticsolvents are preferred with chlorobenzene being most preferred. Thefinal product is obtained in solution and may be recovered by filtrationwhere crystallization has already occurred, or the entire mixture may befiltered and the filtrate concentrated to the point of crystallizationor by other techniques known in the art. M I

The reaction may also be carried out by first forming the acid chlorideof the substituted salicylic acid compound by refluxing the acid in asolvent such as benzene, toluene, or xylene with a halogenating agentsuch as thionyl chloride, oxalyl chloride, or phosphorous trichloride.The solvent is then removed before reacting the acid halide with theamine. Any suitable method may be employed, such as distillation invacuo, particularly for the lower boiling solvents. The residue is thenredissolved in the same solvent and the solution is In order to maximizeyields of Compounds I, it may be desirable in some case to protect thephenol group of Compounds 11 to eliminate the possibility of interactionbetween the acid halide group of one molecule of Compounds II with theunprotectedphenol group of another or with that of the product. This'may be achieved by acylating Compounds II'before use, using preferablyacetylation with, for example, 'acetic anhydride.

- Illustrative of the salicylic be employed are: i

3,5-dibromo salicylic. acid 3,5-dichloro salicyclic acid I 3,5-diiodosalicylic acid 3-nitro-5-bromo-salicylic acid 3-bromo-'5-nitro salicylicacid 3-nitro salicylic acid 3-nitro-5-chloro salicylic acid3,5,6-tribrorr1o salicylic acid 3,5,6-trichloro salicylic acid3,5-dibromo-6hydroxy salicylic acid 5-nitro salicylic acid3-trifluoromethyl-5-bromo salicylic acid o-acetyl-3,5-dibromo salicylicacid 5-iodo-3-nitro salicylic acid 4-trifluoromethyl salicylic acid, andthe like. Representative of the amines which may be employed are:

4-aminobiphenyl ether 4-amino-3'-trifluoromethyl biphenylether4-amino-4'-methoxybiphenyl ether 4-amino-3'-ethoxybiphenyl ether4-amino-4'-nitrobiphenyl ether 4-amino-2'-nitrobiphenyl ether4-amino-4'-cyanobiphenyl ether 4-amino-4'-bromobiphenul ether4-amino-4'-chlorobiphenyl ether 4-amino-2'-chlorobiphenyl ether4-amino-2'-bromobiphenylether 4-amino-2-chlorobiphenyl ether4-amino-2'-bromobiphenyl ether 4-amino-4'-fluorobiphenyl ether acidcompounds that may 4-amino-3 '-iodobiphenyl ether4-amino-2-trifluoromethyl-4'chlorobiphenyl ether4-amino-3'-methyl-4'-chlorobiphenyl ether 4-amino-2,4'-chlorobiphenylether 4-amino-2,4'-bromobiphenyl ether 4-amino-2-chloro-3'-bromobiphenyl ether 4-amino-2,4'-dichloro-3 '-methylbiphenyl ether4-amino-2,4-dichloro-3 -propylbiphenyl ether 4-amino-2-methoxy-3',4'-dichlorobiphenyl ether 4-amino-2-ethoxy-3 ',4'-dichlorobiphenylether 4-amino-2,2 '-dichloro-4 '-methylthiobiphenylether4-amino-2,4,6-trichlorobiphenyl ether 4-amino-2,2',4'-trichlorobiphenylether 4- am ino-2,2,4'-tribromobiphenyl ether4-amino-2,2',4',6'-tetrachlorobiphenyl ether 4-amino-4-bromobiphenylthioether 4-amino-4'-nitrobiphenyl thioether 4-aminol-(p-bromobenzenesulfonyl )-benzene 4-aminol-(p-nitrobenzenesulfonyl)-benzene4-amino-1-(p-bromobenzenesulfinyl)-benzene 4-aminol-(p-nitrobenzenesulfinyl)-benzene 4-aminobiphenyl ketone5-amino-2,4'-dichlorobiphenyl ether 5-amino-2,4-dichlorobiphenylthioether 5-amino-2,4-dibromobiphenyl ether 4-amino-3,4-dichlorobiphenyl ether 4-amino-2,4',5-trichlorobiphenyl ether4-amino-3 ,4 '-dichlorobiphenylether 4-amino-3-trifluoromethylbiphenylsulfide, and

3-amino-3 -trifluoromethylbiphenyl ether.

The amine reactants of Formula IV wherein Q is S or O and in which thephenoxy or phenylthio group is para to the amine nitrogen atom (suchcompounds hereafter designated Compounds lV-a) are prepared in a seriesof reactions depicted in the following flow diagram: 10

m Ha I 09in & HQ

phenylthio group in Compound IV(a) is positionedpara to the aminonitrogen atom. Such compounds when used in the preparation of CompoundsI will yield what has been heretofore referred to as the 4- isomer.Where the meta position of Q relative to the amino group in Compounds IVis desired, a modification of the above procedure, as more specificallyshown hereinafter, is effective to achieve such a result.

More particularly, Step A of the above procedure involves reacting thep-halonitrobenzene with the phenol or thiophenol in a fusion reaction.The fusion itself involves heating the reactants to their molten state,optionally in the presence of a catalyst such as metallic copper,cuprous chloride, cupric chloride, and the like. The reaction must becarried out in the presence of a base such as potassium hydroxide,sodium hydroxide, sodium hydride, sodium methoxide, potassium carbonate,sodium carbonate, potassium bicarbonate, sodium bicarbonate, or thelike. Solvents may be employed, if desired, and suitable results areobtained with dimethylformamide, dimethylsulfoxide, biphenylether,ethanol, methanol, and the like. A convenient temperature for either afusion or solution reaction is in the range of from 25300C. Thenitrodiphenyl product of the reaction is obtained as a solid and may berecrystallized in accordance with well-known techniques.

Step B in the preparation of Compounds IV'(a)contemplates reducing thenitrodiphenyl compounds from Step A (Compound V) to convert the nitrogroup thereof to the amino group. Any system capable of reducing nitrogroups may be employed provided due consideration is given tomaintaining the rest of the molecule intact. For example, catalyticreductions using hydrogen and Raney nickel or platinum may be employed.Chemical reductions using metals such as iron or zinc in the presence ofacids may also be used. Catalytic hydrogenations are preferred and areconveniently run at room temperature at a hydrogen pressure of fromabout to 100 p.s.i.g. Where any of X and Z are reducible groups such asnitro or cyano, for example, selective reduction of the desired groupmay be achieved by known techniques, as for example, by employing onlyone equivalent of hydrogen or by using mild reducing agents such ashydrogen sulfide or salts thereof.

To obtain Compounds IV wherein the point of attachment of Q is meta tothe amino group, Compounds IV(a) are subjected to a series of reactions,the effect of which is to introduce an amino group or a group which canbe converted to an amino group at the appropriate position. In general,this is achieved by blocking the amino group of Compound IV(a) with anacyl group using, for example, acetic anhydride, nitrating the compoundwith a suitable nitrating system, for example, an aceticanhydride-nitric acid system, then removing the acyl group by hydrolysiswith, for example, sodium hydroxide, potassium hydroxide, or the like,then diazotizing the free amine, and reductively eliminating theresulting diazo group, all in a manner known in the art. The newlyintroduced nitro group is then reduced to the amino group in the mannerdescribed for Step B above and is then available for reaction with thesalicylic acid Compound III. The phenylthiosalicylanilides can becoverted to the corresponding phenylsulfonylsalicylanilides andphenylsulfinylsalicylanilides.

Compounds V or Compounds I wherein Q is sulfur are oxidized bytechniques well known in the art of converting sulfides to sulfinyl orsulfonyl groups, as, for example, by using hydrogen peroxide, chromicacid, or potassium permanganate or the like. t

The compounds of the present invention have utility in the field ofanimal therapy. They are effective anthelmintics and are especiallyeffective against both mature and inmature liver fluke of the speciesFasciola gigantica and Fasciola hepatica, the common liver fluke insheep and cattle. Many of the compounds of the invention also possessactivity against nematodes and particularly against Haemonchus contortusof sheep, and some of the compounds show marked activity againstmigrating ascarids in swine. This is especially true of the compoundswherein Y is nitro. For example, the antiascarid activity of3-nitro-'5-bromo-3-chloro- 4'-(p-chlorophenoxy)-salicylanilide at themigratory stages of Ascaris suum in swine shows a marked reduction inlung pathology, and the number of larvae reaching the lungs during theinitial stage' of infection. For effective treatment, certain dosagelevels are desired depending upon the compound employed, the type ofanimal to be treated, and the particular helminth being combatted. Ingeneral, effective fluke efficacy is achieved when the compound isadministered in a single dose at dosage levels of from about 1 to 300mg./kg. of animal body weight, and preferablyfrom about 2 to 50 mg./kg.of animal body weight. The compounds of the present invention may beadministered in a variety of ways, depending upon the particular animalemployed, the type of anthelmintic treatment normally given to such ananimal, the materials employed, and the particular helminths beingcombatted. It is preferred to administer them in a single efficaciousoral or parenteral, most preferably oral, does at a time when fluke ornematode infection is apparent or suspected.

They may be employed alone or in combination with other anthelmintics,parasiticides or antibacterials.

In general, compositions containing the active anthelmintic compound areemployed; the amounts. of the anthelmintic ingredient in thecomposition, as well as the remaining constituents varying according tothe type of treatment to be employed, the host animal, and theparticular parasitic disease being treated. In general, however,compositions containing a total weight percent of the active compound orcompounds ranging from 0.001 to 95% will be suitable with the remainderbeing any suitable carrier or vehicle. Furthermore, the compositionsshould contain enough of the active compound to provide an effectivedosage for the proper treatment of the parasitic disease.

A number of modes of treatment may be employed, and each to some extentdetermines the general nature of the composition. For example, theanthelmintic compounds may be administeredto domesticated animals in asingle unit oral dosage form such as a tablet, bolus, capsule or drench;in a liquid'oil base form suitable for parenteral administration; orthey may be compounded as a feed premix to be later admixed with theanimals food.

When the compositions are to be solid unit dosage forms as in tablets,capsules, or boluses, the ingredients other than the active compoundsmay be any other pharmaceutically acceptable vehicles convenient in thepreparation of such forms, and preferably materials nutritionallysuitable such as starch, lactose, talc, magnesium stearate, vegetablegums, and the like. Moreover, when capsules are employed, the activecompound may be used in essentially undiluted form, the only extraneousmaterial being that of the capsule casing itself which may be hard orsoft gelatin material. When the dosage form is to be used for parenteraladministration, the active material is suitably admixed with anacceptable oil base vehicle, preferably of the vegetable oil variety,such as peanut oil, cottonseed oil, and the like. In all of such forms,i.e., in tablets, boluses, capsules, and oil base formulations, theactive compound conveniently ranges from about 5 to by weight of thetotal composition.

When the unit dosage form is to be in the form of a drench, theanthelmintic agents may be mixed with agents which will aid in thesubsequent suspending of the active compound in water, such asbentonite, clays, water soluble starches, cellulose derivatives, gums,surface active agents and the like to form a dry predrench composition,and this predrench composition added to water just before use. In thepredrench formulation, in 'addition to the suspending agent, suchingredients as preservatives, antifoam compounds, and the like may beingcontributed by the excipients. Preferably, the solid compositioncontains from 30% to 95% by weight of the active compound. Enough watershould be added to the solid product to provide the proper dosage levelwithin a convenient amount of liquid for a single oral dose. Thecommonly used measure in the field is one fluid ounce of material andthus that one fluid ounce of material should contain enough of theanthelmintic compound to provide the effective dosage level. Liquiddrench formulations containing from about to 30 weight percent of dryingredients will in general be suitable with the preferred range beingfrom 15 to 50 weight percent.

Where the compositions are intended to be used as feeds, feedsupplements or feed premixes, they will be mixed with suitableingredients of an animals nutrient ration. The solid orally ingestiblecarriers normally used for such purposes, such as distillers driedgrains, corn meal, citrus meal, fermentation residues, ground oystershells, Attapulgus clay, wheat shorts, molasses solubles, corn cob meal,edible vegetable substances, toasted dehulled soya flour, soybean millfeed, antibiotic mycelia, soya grits, crushed limestone and the like areall suitable. The active compounds are intimately dispersed or admixedthroughout the solid inert carrier by methods such as grinding,stirring,milling or tumbling. By selecting proper diluents and by altering theratio of carrier to active ingredient, compositions of any desiredconcentration may be prepared. Feed supplement formulations containingfrom about 10 to 30% by weight of active ingredient are particularlysuitable for addition to feeds. The active compound is normallydispersed or mixed uniformly in the diluent but in some instances may beabsorbed on the carrier.

These supplements are added to the finished animal feed in an amountadequate to give the final concentration desired for controlling ortreating the helminth infection by way of the animal ration. Althoughthe preferred level in feeds will depend on the particular compoundsbeing employed, the active compounds of this invention are normally fedat levels of 0.2525% in the feed. As stated above, animals arepreferably treated at a time when the infestation is apparent orsuspected and the most preferred method for such treatment is via thesingle oral dose technique. Thus, administration of medicated feed isnot preferred but may certainly be employed. Similarly, the amounts ofdrug present in the feed may be reduced to levels in the order of 0.001%to 3.0 weight percent based on the weight of feed, and the medicatedfeed administered over prolonged periods. This would be in the nature ofa preventive or prophylactic measure but again is not the mode ofchoice. Another method of administering the compounds of this inventionto animals whose feeds are conveniently pelleted, such as sheep, is toincorporate them directly in the pellets. For instance, the anthelminticcompound is readily incorporated in nutritionally adequate alfalfapellets at levels of 2 to 110 grams per pound of pellets for therapeuticuse, and at lower levels for prophylactic use, and such pellets fed tothe animals.

In addition to their use in the treatment of helminthiasis, thesalicylanilides which are the subject of this invention are activeantibacterial agents and, in particular, are effective againstStaphylococcus aureus, Staphylococcus albus, Streptococcus faecalis,Escherichia coli, Pseudomonas geruginosa, and Proteus vulgaris. Thesalicylanilidesof this invention may be used in the treatment of a widerange of skin conditions. Although they exhibit marked topical activityper se, they can be employed as an additive in such preparations assoaps, germicides, deodorants, household disinfectants, dust powders,skin creams, medicated lotions, and cosmetics. The high activity againstStaphylococcus aureus is of considerable interest, since this organismis common on the skin and is associated with many wound infections. Therange of activity is wide and includes gram positive and gram negativeorganisms, and some fungi. Although the halogenated salicylanilides maybe used as a component of creams'and powders, etc., it is alsocontemplated that they may be incorporated into the formula tions ofantiseptic aerosol products.

The following examples are given for the purpose of illustration andnotby way of limitation:

EXAMPLE 1 3 ,5-Dibromo-3 'Chloro-)4 '-p-Chlorophenoxy)- SalicylanilideThis example is illustrative of the general procedure for obtaining thesalicylanilides of the present invention wherein Q in compound I is parato the amino nitrogen atom.

2-Chloro-4-nitrophenyl-p-chlorophenyl ether A mixture of 108 g. (0.842mole) of p-chlorophenol, 58 g. of potassium hydroxide is stirredmechanically in a one-liter three-neck flask equipped with a thermometeruntil a homogeneous solution is obtained. During this time, about 10minutes, the temperature is observed to rise to about C. Then 90 g. of a173 g. (0.901 mole) portion of 3,4dichloronitrobenzene is added and thetemperature raised carefully to ca. C. An exothermic reaction beginswhich causes the temperature of the reaction mixture to increase to150C. The temperature is allowed to fall to 120C. again and theremaining 83 g. of the dichloronitrobenzene added. The mixture is heatedslowly to C, the exothermic reaction again begins, and causes thetemperature to increase to about C. The reaction mass is cooled to110C., then 250ml. of water is added quickly with vigorous stirring, toobtain a crystalline precipitate. The mixture is filtered, washed withwater and the solid then dissolved in 800 ml. of boiling ethanol. Thesolution is boiled down until crystallization starts. The ether isobtained as yellow crystals, 142 g., m.p. 105107C. Uponrecrystallization from boiling ethanol, 136 g. of2-chloro-4-nitrophenyl-pchlorophenyl ether, m.p. 106108C., are obtained.

b. 4-Amino-2-chlorophenyl-p-chlorophenyl ether The 136 g. of2-chloro-4-nitrophenyl-p-chlorophenyl ether obtained in step a. ishydrogenated at room temperature at 40 lbs. hydrogen pressure in 800 ml.of ethanol with 4 teaspoons of Raney nickel until the theoretical amountof hydrogen is taken up (8 hours).

The catalyst is removed by filtration and the solvent is stripped offcompletely under high vacuo giving b 132 g. of a brown oil whichsolidifies to a grey solid, m.p. 7274C. This is used without furtherpreparation for the next step.

c. 3 ,5-Dibromo-3 '-chloro-4 '-(p-chlo rophenoxy salicylanilide 62.3 g.(0.245 mole) of 4-amino-2-chlorophenyl-pchlorophenyl ether and 72.5 g.(0.245 mole) of 3,5- dibromo salicylic acid are suspended in 725 ml. ofchlorobenzene and stirred mechanically. 8.6 ml; of phosphorustrichloride is added in a slow stream. The mixture is heated to boilingand refluxed for 3 hours, filtered hot, and concentrated in vacuo to ca.450 ml. A

phenols, there are obtained the corresponding thioethers which areconverted to the corresponding phenylthio salicylanilides.

EXAMPLES 7 17 thick slurry forms which is allowed to come to roomtemperature, aged 2 hours, filtered and washed with3,5-Dibr0m0-3'-Chloro-4'-(p-Chloro-m-Methylpetroleum benzin. It is driedin vacuo at 50C. for 24 phenoxy)-Salicylanilide 0 O laours, grvmgfiS g.of cfr ude product, m.p. 1f63b-l65 C. A mixture of 45 g (017 mole) ofrlecrysga P g? a gg f f dichloro-3-methylbiphenyl ether, 48.6 g. of 3,5-P s? 1 ig- 22" dibromosalicylic acid 0.17 mole) and 6.1 ml. 0.07 4 Penoxy)'sa Icy am 1 mole) of phosphorus trichloride in 1000 ml. ofchloroare m benzene is stirred and refluxed for 3 hours. The reac-EXAMPLES 2 6 tion mixture is filtered hot through a sintered glass fundE f l d nel. The filtrate is then concentrated on a steam bath T gewaralproce me of Xample 010w? under vacuum of about 15 to mm. of mercury toreusmg equlvale!" amOuPtS of 9 m move solvent. The product is thenrecrystallized from Place fi ;i i m 3 1th the benzene yielding 33 g. of3,5-dibromo-3-chloro-4'-(pphenos s own in t e ta e e ow to pro uce t ecorrechloro m methylphenoxy) salicylanilide; sponding ether which 18then reduced in accordance Step pmquce the ammo (fompound h m 20 Whenthe above procedure is repeated using equivah table T compozlmd ls l awlth lent amounts of the ether compound shown below in d1bromosal1cyl1lcacii d 1n accor ance wit step c. to proplace of the 4 amino 27 4Idich1oro 3I methylbiphen duce the Sahcy am lde shown ylether, theindicated salicylanilide is obtained.

Melting Example Ether salicylanilide Point 8 4-aminophenyl-p-3,5,-dibromo-4'-(pbromophenylether bromophenoxy)- salicylanilide 172-173C. 9 4-arninophenyl-p- 3,5-dibromo-4'-(pchlorophenylchlorophenoxy)-ether salicylanilide 1 66-1 68C. 10 4-aminophenyl-o- 3,5-dibromo-4-(ochlorophenylchlorophenoxy)- ether salicylanilide 161-162C. l l4-aminophenyl-o- 3,5-dibromo-4'-(obromophenylether bromophenoxy)-salicylanilide 1 70-1 7 1C. 12 4-am ino-2-chloro- 3 ,5-dibromo-3-chlorodiphenylether 4'-phenoxy)- salicylanilide 148-l 49C. l34-aminophenyl-m- 3,5-dibromo-4'-( mbromophenylether bromophenoxy)-salicylanilide 1 58-1 60C. 14 4-aminophenyl-p- 3 ,5-dibromo-4'-(pfluorophenylether fluorophenoxy)- salicylanilide 1 29-1 30C. 154-amino-2-trifluoro- 3 ,5-dibromo-3'-trimethylphenyl-pfluoromethyl-4-(pchlorophenylether chlorophenoxy)-salicylanilide 8S-87C.

(as etherate) l6 4-aminophenyl-m- 3,5-dibromo-4'-(mmethyl-p-chloromethyl-p-chlorophenylether phenoxy)-salicylanilide l49-l 50C. 1 7 4-amino-2-methoxy- 3 ,5-dibromo-3phenyl-m,p-dichloromethoxy-4'-(m,pphenylether dichlorophenoxy)-salicylanilide l 83-184C.

Phenol Melting Example Compound Ether salicylanilide Point 2 phenol4-aminophenyl- 3,5-dibromo-4' phenyl ether phenoxysalicylanilide 152-153C. 3 m-trifluoro- 4-aminophenyl- 3,5-dibromo-4'- ll5ll7C.

methylm-trifluoro- (m-trifluorophenol methyl phenyl methylphenoxy)-ether salicylanilide 4 p-methoxy- 4-aminophenyl- 3,5-dibromo-4'- phenolp-methoxy- (p-methoxyphenoxy)- phenylether salicylanilide l98.5-200C. 5p-cyano- 4-aminophenyl- 3,5-dibrom0-4'- phenol p-cyanophenyl(p-cyanophenoxy)- ether salicylanilide 225-227C. 6 p-nitro4-aminophenyl- 3,5-dibromo-4- phenol p-nitrophenyl- (p-nitrophenoxy)-ether salicylanilide 214-216C.

When the above procedures are repeated using, in place of the phenolsdescribed, the corresponding thio- The ethers used in Examples 7-l7 areprepared in accordance with the procedure of Example 1 (a) and (b) Amixture of 25.4 g. (0.1 mole) of 4-amino-2,4'- dichlorobiphenyl ether,20.7 g. (0.1 mole) of 3,5-

dichlorosalicylic acid, and 3.5 ml. of phosphorus trichloride in 300 ml.of chlorobenzene is stirred and refluxed for 3 hours. It is filtered hotand the filtrate cooled in an ice bath for 3 hours. The resultingcrystals are filtered and washed with petroleum benzin to give 32 g, ofproduct, m.p. l59162C. It is recrystallized three times from benzene'togive 16.1 g. of 3,3',5- trichloro-4-(p-chlorophenoxy)-salicylanilide,m.p. 16l.5-162.5C.

The above procedure is repeated using equivalent amounts of thereactants shown below to produce the salicylanilide indicated:

EXAMPLE 24 3 ,5-Dibromo-6-Hydroxy-4 '-Chloro-3 p-Chlorophenoxy)-Salicylanilide A mixture of 6.05 g. of 2,6-dihydroxy benzoic acid,10.0 g. of 5-amino-2,4-dichlorobiphenyl ether, and 1.35 ml. ofphosphorus trichloride in 100 ml. of chloro benzene is refluxed for 3hours. Upon standing at room temperature, the crude product settles outof the reaction mixture. Recrystallization from a mixture ofbenzene-ethyl acetate yields 10.3 g. of 6-hydroxy-4'- chloro-3p-chlorophenoxy )-salicylanilide, m .p. l99-202C.

10.03 g. of 6-hydroxy-4'-chloro-3'-(p-chlorophenoxy)-salicylanilide isdissolved in 620 ml. of ether. 2.68 ml. of bromine is added dropwise, atroom temperature with stirring. Upon addition of 300 ml. of a mixture ofpetroleum benzin, the crude product settles out. Recrystallization fromether-petroleum benzin yields 1.0

' g of3,5-dibromo-6-hydroxy-4'-chloro-3'-chloro-3-(pchlorophenoxy)-salicylanilide,m.p. 171l73C., dec.

Salicylic Ether Melting Ex. Acid Compound Compound salicylanilide Point19 3-bromosali- 4-amino-2-chloro- 3-bromo-3- 201-202C.

cyclic acid phenyl-p-chlorochloro-4'- phenyl ether chlorophenoxy)-salicylanilide 20 3,5,6-tri- 4-a.mino-2-chloro- 3,5,6-tribromo-234-235C.

bromosaliphenyl-p-chloro- 3 '-chloro-4'-( pcylic acid phenyletherchlorophenoxy)- salicylanilide 21 3,5,6-tri- 4-amino-2-chloro-3,5,6-trichloro- 21 l2l2-"C.

chlorosali- 4-phenyl-p-chloro- 3'-chloro-4'-(pcylic acid phenyl etherchlorophenoxy)- salicylanilide 22 3,5-dibromo- 4-amino-2-chloro-3,5-dibromo-6- 202 dec.

6-hydroxyphenyl-p-chloro-mhydroxy-3 '-chlorosalicylic methylphenyl ether4'-(p-chloro-macid methylphenoxy)- salicylanilide EXAMPLE 23 EXAMPLE 253 ,5-Dibromo-6-l-1ydroxy-3 '-Chloro-4'-(p-Chlorophenoxy)-Salicyl'anilide A mixture of 13.8 g. (0.09 mole) of2,6-'

added dropwise at room temperature with stirring.

After the addition of bromine is complete, the reaction mixture iscooled in an ice bath, and the crude product settles out of the ethersolution. Recrystallization from benzene yields 4.5 g. of3,5-dibromo-6-hydroxy-3 chloro-4'-(p-chlorophenoxy)-salicylanilide, m.p.l87-188C., dec.

4-Amino-4'-Fluorodiphenyl Sulfide A solution of 30 g. of4-fluoro-4-nitrophenylsulfide in 300 ml. of ethanol is reduced at roomtemperature with hydrogen and 2.5 g. of Raney nickel catalyst under 40pounds of pressure. After the theoretical amount of hydrogen isabsorbed, the catalyst is reduced by filtration, and the filtrate isconcentrated in vacuo to an oil, which solidifies on standing. Afterpulverizing the solid in a mortar andwashing with petroleum benzin, 24g. of substantially pure 4-amino-4'-fluorodiphenyl sulfide, m.p.63-65C., are obtained.

EXAMPLE 26 3 ,5-Dibromo-4'-(p-Fluorophenylthio )-Salicylanilide Amixture of 24.3 g. of 4-amino-4'- fluorodiphenylsulfide, 32.8 g. of3,5-dibromo salicylic acid, and 3.9 ml. of phosphorus trichloride in 340ml. of chloro benzene is refluxed for 3 hours. The mixture is filteredwhile still hot, and the filtrate is concentrated to a small volumeuntil crystallization occurs. 50 cc. of petroleum benzin are added tocomplete the crystallization. Upon recrystallization of the crudeproduct from methanol, 43 g. of 3,5-dibromo-4'-p-fluorothiosalicylanilide, m.p. l54157C., are obtained.

EXAMPLE 27 3,5-Dibromo-4'-(p-Fluorophenylthio )-6-Methoxy SalicylanilideA mixture of 5.0 g. of 6-methoxy salicylic acid, 6.52 g. of4-amino.-4'-fluorodiphenyl sulfide, and 1.56 ml. of phosphorustrichloride in 105 ml. of chlorobenzene is stirred at room temperaturefor 30 minutes after which it is refluxed for 3 hours. The reactionmixture is allowed to cool to room temperature and is concentrated invacuo to an oil. The oil is crystallized from 60 ml. of ethanol toafford 4'-( p-fluorophenylthio)-6-methoxy salicylanilide, m.p. l09l 10C.

1.0 g of 4-(p-fluorophenylthio)-6- methoxysalicylanilide is dissolved inml. of warm glacial acetic acid. A solution of 0.3 ml of bromine in 2ml. of glacial acetic acid is added at 65C. After all of the bromine isconsumed, the reaction mixture is poured onto ice, and the solid formedis collected by filtration. Upon recrystallization from ether-petroleumbenzin, pure 3,5-dibromo-4-'-(p-fluorophenylthio)-6- methoxysalicylanilide, m.p. ll2l 13C. is obtained.

EXAMPLE 28 3 ,5-Dibromo-6-hydroxy 4'-(p-fluorophenylthio)-Salicylanilide A mixture of 23.0 g. (0.149 mole) of2,6 dihydroxybenzoic acid, 32.6 g. (0.149 moles) of 4-amino-4'-fluorobiphenyl sulfide, and 5.2 ml. of phosphorus trichloridein 450 ml. of chloro benzene is refluxed for 3 hours. Upon standing atroom temperature, the crude product settles out of the reaction mixture.The crystals are filtered off, and recrystallization from methanolyields 34.4 g. of 6-hydroxy-4-(pfluorophenylthio)-salicylanilide, m.p.l69l72C.

5.0 g. of 6-hydroxy-4'-(p-fluorophenylthio)- salicylanilide is dissolvedin 250 ml. of ether. 1.44 ml. of bromine is added dropwise withstirring. The solution is then concentrated in vacuo to an oil. The oilis dissolved in 55 ml. of benzene from which crystallizes upon cooling2.1 g. of 3,5-dibromo-6-hydroxy-4-(pfluorophenylthio)-salicylanilide,m.p. 167C., dec.

EXAMPLE 29 3 ,5-Diiodo-3 '-Chloro -4 p-Chlorophenoxy Salicyanilide Amixture of 31.0 g. of 4-amino-2,4- dichlorobiphenyl ether, 47.4 g. of3,5-diiodo salicylic acid, and 4.3 ml. of phosphorus trichloride in 235ml. of chloro benzene is refluxed for 3 hours. The hot solution isdecanted from some insoluble residue and the crude product settles outof solution upon cooling to room temperature. Upon recrystallizationfrom benzene, 27.8 g. of3,5-diiodo-3-chloro-4'-(p-chlorophenoxy)-salicylanilide, m.p. 168-170C.is obtained.

\ EXAMPLE 30 3 ,3 ,5-Tribromo-4 (p-Bromophenoxy)-Salicylanilide Amixture of 18.4 g. (0.0534 mole) of 4-amino-2,4'- dibromobiphenyl ether,15.8 g. (.053 mole) of 3,5- dibromo salicylic acid and 1.82 ml. ofphosphorus trichloride in 150 ml. of chlorobenzene is stirred andreluxed for 3 hours. It is filtered hot and the filtrate cooled to roomtemperature overnight. Green crystals form which are filtered. Thefiltrate is washed with 2.5

N hydrochloric acid (25 ml.) and 25 ml. of a saturated sodium chloridesolution. The organic layer is dried over magnesium sulfate solution,concentrated to a solid mass which is combined with the first crop. Thesolid is recrystallized twice from benzene, treated with charcoal, andrecrystallized four times from benzene to yield 12 g. of3,3',5-tribromo-4-(p-bromophenoxy) salicylanide, m.p. l85186C.

EXAMPLE 31 3,5-Dibromo-3 -Chloro-4-(o,p-Dichlorophenoxy Salicylanilide Amixture of 38.2 g. (0.132 moles) of 4-amino- 2,2',4'-trichlorobiphenylether, 39.1 g. (0.132 mole) of 3,5-dibromo salicylic acid and 4.5 ml.phosphorus tri-. chloride in 350 ml. of chlorobenzene is stirred andrefluxed for 3 hours. It is filtered hot and the filtrate cooled at roomtemperature for 2 hours. White crystals (40 g.) are obtained which arerecrystallized three times from benzene and twice from ethanol to yield23.9 g. of 3,5-dibromo-3'-chloro-4'-(o,p-dichlorophenoxy)-salicylanilidem.p. l49-15 1C.

EXAMPLE 32 3,5-Dibromo-3 -Chloro-4'-(m,p-Dichlorophenoxy SalicylanilideA mixture of 37.5 g. (0.13 moles) of 4-amino-2,3',4'- trichlorobiphenylether, 37.2 g. (0.13 mole) of 3,5- dibromo salicylic acid and 4.4ml ofphosphorus trichloride in 400 ml. of chlorobenzene is stirred andrefluxed for three hours. It is filtered hot and the filtrate cooled toyield white crystals. It is recrystallized twice from benzene yielding32 g. of 3,5-dibromo-3'-chloro-4- (m,p-dichlorophenoxy)-salicylanilide,m.p. 193.5l94.5C.

EXAMPLE 33 5-Bromo-3-Nitro-3 '-C hloro-4 '-(p-ChlorophenoxySalicylanilide 'A mixture of 33.3 g. (0.132 mole) of 4-amino-2,4'-dichlorobiphenyl ether, 34.4 g. (0.132 mole) of 5- bromo-3- nitrosalicylic acid and 4.5 ml. (0.0513 mole) of phosphorus trichloride in350 ml. of chlorobenzene is stirred and refluxed for 3 hours in a1-liter flask. It is filtered hot and the filtrate allowed to cool andconcentrate to a dark oil. 25 ml. of benzene is added and allowed tostand overnight. The crystals are filtered and washed twice with benzeneover a sintered glass funnel. They are then recrystallized once fromethanol and then dissolved in ml. of dimethylformamide and 25 ml. ofwater to which 250 ml. of ethanol is added. This is then heated untilcomplete solution occurs. The solution is then cooled slowly to roomtemperature and then in ice until crystallization is complete. It isfiltered, washed with ethanol and dried in vacuo at 50C. to yield 42.0g. of 5-bromo-3-nitro-3'-chloro-4-(pchlorophenoxy)-salicylanilide, m.p.l50-l52C.

Using equivalent amounts of 5-nitro salicylic acid or 3-bromo-5-nitrosalicylic acid in place of the 5-bromo- 3-nitro salicylic acid in theforegoing procedure results in 5-nitro-3 -chloro-4 -(p-chlorophenoxysalicylanilide (m.p. 200202C.) or 3-bromo-5nitro- EXAMPLE 34 3 ,5-Dibromo-4 -Cliloro-3 '-(p-Chlorophenoxy Salicylanilide This example isintended to be illustrative of a procedure for the preparation of thosesalicylanilides of the present invention wherein Q in Formula I is metato the amide nitrogen. Example 1 a. and b. is repeated to produce4-amino-2-chlorophenyl-p-chlorophenyl ether. The ether so produced (10g.) is then acetylated with 10 ml. of benzene and 6.5 m1. of aceticanhydride by stirring at room temperature for 15 minutes. It is thencooled and the product allowed to crystallize. Filtration gives 12 g. of4-acetylamino-2,4'-dichlorobiphenyl ether, m.p. 142143C. 10 g. of thisproduct is suspended in 100 ml. acetic anhydride and cooled to C. It isthen nitrated by dropwise addition of a solution of 5.35 ml. ofconcentrated nitric acid and 1.78 ml. of acetic anhydride with vigorousstirring while the temperature is maintained at 0C. After the additionis complete, it is stirred for an additional hour at 0C. It is thenpoured into 300 ml. of ice water and the product allowed to crystallize.Filtration gives 6.6 g. of 4- acetylamino-2,4'-dichloro-S-nitrobiphenylether, m.p. l32 l36C. This is recrystallized twice from ethanol to give4 g. with a melting point of l45146C.

lg. of the nitro compound so produced is boiled in ml. of ethanol on thesteam bath. A solution of 0.75 g. of'potassium hydroxide in 2 ml. ofwater is added. It is heated for 15 minutes on the steam bath. Theproduct is allowed to crystallize at room temperature, is filter'ed, andwashed with 30% aqueous ethanol to give 750 mg. of4-amino-2,4'-dichloro-5-nitrobiphenyl ether, m.p. l86l88C.

, A solution of 0.6 g. of the above product in 75 ml. of ethanol and 3.2ml. of concentrated sulfuric acid is refluxed with vigorous stirring. Tothe resulting solution is added a solution of 3.05 g. of sodium nitratein 7 ml. of water as rapidly as the gas evolution allows. Reflux iscontinued for one hour after the addition is complete. The reaction isfiltered hot and the filtrate is con centrated in vacuo to about 25 ml.It is then diluted with water until crystallization starts. The 2,4-dichloro-S-nitrobiphenyl ether is recrystallized from ethanol, then frompetroleum benzin ether to a melting point of 93C. The product ishydrogenated in accordance with the procedure set forth in Example 1b.The so obtained crude 5-amino-2,4'-dichlorobiphenyl ether' is usedwithout purification for the next step.

The mixture of 9 g. of the above obtained amine, 12.6 g. of dibromosalicylic acid and 1.45 ml. of phosphorus trichloride in 150 ml. ofchlorobenzene is stirred and refluxed for three hours. It is filteredhot and then concentrated to oil. This is crystallized from benzene andrecrystallized from aqueous ethanol to give 1 1 g. of3,5-dibromo-4-chloro-3'-( p-chlorophenoxy)-salicylanilide, m.p. l65-167C.

' When the above procedure isrepeated using equivalent amounts of any ofthe phenol compounds or phenylthio compounds hereinbefore described inplace of p-chlorophenol and using equivalent amounts of any of thehalonitrobenzenes hereinbefore described in place of the3,4-dichloronitrobenzene, the corresponding salicylanilide having the Qof Formula I attached meta to the amide nitrogen atom is obtained.

EXAMPLE 35 3,5 -Dibrorno-4-(p-Bromobenzenesulfonyl salicylanilide Amixture of 28.2 g. of 4-amino-4'-bromobiphenyl sulfone, 25.8 g. of3,5-dibromo salicylic acid and 2.5 ml. of phosphorous trichloride in 300ml. of chlorobenzene is refluxed with vigorous stirring for three hours.The hot solution is filtered and concentrated until crystallizationstarts. The crystals are filtered and recrystallized fromdimethylformamide to give 47 g. of 3,5-

dibromo-4'-(p-bromo-benzenesulfonyl)-salicylanilide,

biphenyl sulfoxide in place of the bipheny] sulfone.

EXAMPLE 36 Rats are experimentally infected with the sheep liver flukeFasciola hepatica and kept on a normal diet. The infection is allowed toproceed on a natural course for 12 weeks. The rates are then treatedwith a single oral dose of the compound shown in the table below as anaqueous suspension containing 2% methyl cellulose. The medicament isadministered at a level of 300 mg./kg. of animal 'body weight. At thetime of treatment, the animals'weigh about 450 g. About 5 days aftertreatment the rats are necropsied and their bile ducts examined for theextent of infection. The results are summarized in" the table below:

salicylanilide *Dcsignation given when all liver fluke present in bileduct are dead. Indicate some liver fluke present (alive).

EXAMPLE 37 Groups of three animals experimentally infected with thesheep stomach worm Haemonchus contortus are treated nine days afterinfection with a single oral dose of the cmpounds shown below in theform of an aqueous suspension in 2% methyl cellulose at the dosagelevels shown. The hosts are sacrificed one day later and Bod the stomachexamined for presence of worms. The Dose Sheep Li fl ke number found iscompared to those in the groups re- Drug Rate No. Kg. Live Dead tamed asuntreated controls and the efficacy expressed 3,5 dibmmo 3, chlow 20 21029 0 as percent reduction. 4'-(p-chlorophenoxy)- mgJkg. 228 35 O 66salicylanilide 197 36 O 49 217 38 O 34 220 30 O O 181 3 l l 30 AverageNo. Percent 209 33 0 26 Compound Dosage of Worms Reduction 130 34 0 O 40187 31 0 46 3-nitro-5-bromo-3- 12.5 mg./kg. 27 58 203 33 0 26chloro-4-(p-chlor@ 50.0 mgJkg. 0 100 176 35 0 l2 phenoxy)-sa1icyl- 98 360 57 anilide I79 38 O 26 3-bromo-5-nitro-3'- 12.5 mgJkg. 43 33 160 39 025 chloro-4-(p-chloro- 50.0 mgJkg. 18 72 154 40 0 8 phenoxy( -sa1icy1- I166 41 0 0 anilide 200.0 mgJkg. 0 100 -dlbromo-4 -(p- 100 226 39 17 10Control Group 1 0 63 q p e wmg-lkg. 178 40 0 0 Control Group 2 0 6Ssalicylanilide Control Group 3 0 60 Controls 121 47 O 105 3 l 0 192 0 O208 6 0 EXAMPLE 38 20 Sheep experimentally infected with immature F. he-

patica are treated with the compounds shown below at the dosage levelindicated. Treatment is made orally four weeks after infection, i.e., ata time when the liver fluke are at the immature stage, using gelatincapsules containing the drug. The animals are sacrificed about nineweeks after treatment and their bile ducts and liver examined for thepresence of live or dead fluke. The results are compared with thoseobtained on control groups receiving on medication:

As can be seen from the above table, both compounds significantly reducethe number of live fluke in the treatment animals are compared to thecontrol animals in which the fluke flourish. It will be noted that thiseffect is achieved on immature fluke which are extremely resistant andvirtually non-responsive to known chemotherapeutics.

EXAMPLES 39 51 The procedure outlined in Example 24 is repeated usingequivalent amounts of the reactants shown below to produce thesalicylanilide indicated:

EX. SALICYLIC ACID AMlNE MELTING NO. COMPOUND COMPOUND SALICYLANILIDEPOINT 39 3,5-dibromo S-chloro-Z- 5 -chloro 3 ,S-dibromo- 2 l 4-salicylic acid nitro-4(p- 2-nitro-4'-(p-ch1oro- 216C.

ch1orophenoxy)- phenoxy)-$licylaniline anilide 40 3 ,S-dibromo-2-chloro-4-(p- 2 -chloro-3 ,5 -dibromo- 163- salicylic acidchlorophenoxy)- 4-(p-chlorophenoxy)- 164C. niline salicylanilide 41 3,S-dibromo- 5-chloro-2- 5 '-chl0ro-3 ,S-dibromo- 223- salicylic acidmethoxy-4-(p- 2'-methoxy-4-(p- 225C. chlorophenoxy)- chlorophenoxyaniline salicylanilide 42 3,5-dibromo- 5-chloro-2-5'-chloro-3,5-dibromo- 184- salicylic acid hydroxy-4-(p-2-hydroxy-4'-(p- 185C. ch1orophenoxy)- chlorophenoxy anilinesalicylanilide 43 3,5-dibromo- 2-trifluoro- 3,5-dibrorno-2'- 7679C.

salicylic acid methyl-4-(ptrifluoromethyltrifluoromethyl)-4'-(p-trifluoroaniline methyl)-salicylanilide 44 3 ,S-dibromo-3-nitro-4-( m,p- 3 ,5-dibromo-2 '-nitro- 219- salicylic aciddich1orophenoxy)- 4'-(m,p-dichloro- 220C. anilinephenoxy)-salicylanilide 45 3 ,S-dibromo- 2-chloro-4-(o- 2'-ch1oro-3,S-di- 150- salicylic acid methy1phenoxy)- bromo-4'-(o-methyl- 153C.aniline phenoxy)-salicylanilide 46 3,5-dibromo- 3-chloro-4-(p-3'-chloro-3,5-dibromo- 248- salicylic acid chloro-m-cyano-4'-(p-ch1oro-m-cyano- 250C.

phenoxy)-ani1ine phenoxy)-salicylanilide 47 3,5-dibromo- 3-ch1oro-4-(m,m- 3-chloro-3,5-dibromo- 220- salicylic aciddichloro-p-methyl- 4'-(ni,m'-dichloro-p- 222C. phenoxy)-anilinemethy1phenoxy)- salicylanilide 48 3,5-dibromo- 4-(p-trifluoro-3,5-dibromo-4'-(p- 158- salicylic acid methylphenyl)- trifluoromethyl-159C. aniline phenoxy)-salicy1- anilide 49 3,5-dibromo- 4-(m,m'-ditri-3,5-dibromo-4-(rn.m' 161- salicylic acid fluoromethylditrifluoromethyl-163C. phenoxy)-aniline phenoxy)-salicyl- I anilide 3,5-dibromo-3-chloro-4-( p- 3'-chloro-3,5- 208- salicylic acidch1oro-m,m'-didibromo-4'-(p-ch1oro- 210C.

methy1phenoxy)- m,m-dimethylphenoxy)- aniline salicylanilide 515-bromo-3- 3-ch1oro-4-(p- 5-bromo-3 '-chloro-3- 238- cyanoch1orophenoxy)- cyano-4-(p-chloro- 240C. salicylic acid anilinephenoxy)-salicy1- anilide 25 EXAMPLE 52 chlorophenyl-p-chlorophenylether in 250 ml. of

sodium hydroxide. The reaction mixture is stirred for 60 minutes afteraddition of the acid chloride is complete. The pH of the solution isadjusted to 6, and the crude product settles out of solution. Uponrecrystallization from benzene-petroleum naphtha, pure 3,5- dibromo-3'-chloro-4 -(p-chlorophenoxy salicylanilide, m,p. l64166C., is obtained.I

EXAMPLE 53 3 ,5-Dibromo-3 '-Chloro-4'-(p-Chlorophenoxy)- SalicylanilideTo a solution of 25.4 g. (0.1 mole) of 3-chloro-4-(p--chlorophenoxy)-aniline in 150 ml. of odichlorobenzene isadded 10.1 g.(0.1 mole) of triethyl amine, followed by 5.1 l g. (0.03 mole) ofphosphorous oxychloride with cooling. The mixture is stirred for minutesat 20"-25C., after which 29.6 g. (0.1 mole) of 3,5-dibromosalicylic acidare added, and the resulting solution is refluxed for 3 hours. Thereaction mixture is then cooled, filtered, washed with water, and driedover sodium sulfate. The drying agent is removed by filtration,- and theproduct is precipitated by the addition of n-hexane. Uponrecrystallization from benzene, 3 ,5 -dibromo-3 -chloro-4p-chlorophenoxy)- I Salicylanilide, m.p. l73**C., is obtained.

EXAMPLE 54 3 ,5-Dibromo-3 -Chloro-4 '-(p-Chlorophenoxy)- Salicylanilide5.6 Ml. (0.06 mole) of-phqsphorous trichloride are added at roomtemperature to a solution of 32.5 g. (0.13 mole) of 3-chloro-4-(p-chlorophenoxy)-aniline in 400 ml. of chlorobenzene. Thesolution is allowed to stand for 10 minutes, after which it is refluxedfor 4 hours or until all of the hydrogen chloride is evolved. Thesolution is cooled to room temperature, the insoluble material isfiltered off, and the crude phosphorazo intermediate is obtained byconcentration in vacuo. 5.54 g. 18.7 mmoles) of 3,5-dibromo salicylicacid are added to a solution of Sgrams (9.4 mmoles) of the phosphorazointermediate in 50 ml. of chlorobenzene. The mixture is heated at 110C.for hours, after which it is filtered and concentrated to '40 ml. Theproduct crystallizes upon cooling, is collected by filtration, and afterwashing with cold chlorobenzene and petroleum ether, substantially pure3,5-dibromo- 3 '-ch1oro 4-(p-chlorophenoxy):Salicylanilide, m.p.170173C., is obtained. ,a

EXAMPLE 55v in efficacy tests against mature, naturally occurring F.hepatica infections in sheep, the following compounds are administeredas a single oral dose in a gelatin capsule/Efficacy is determined in themanner set forth in Example 37. The animals are sacrificed about a weekafter dosing. The dosage levels at which effective results are obtainedis indicated:

' Dosage Level COMPOUND Those substances within the purview of Formula 1above wherein A represents an acyl radical such as lower-alkanoyl oraroyl have activity against liver fluke essentially equivalent to thenonacylated compounds. These acyl derivatives are obtained by reactingthe appropriately substituted 2-acylbenzoyl chloride with theappropriately substituted 4-amino-biphenyl, or by acylating theSalicylanilide with an acylating agent, such as acetic anhydride inpyridine. The 2-acyl benzoyl chloride having the Y substituent in thering is obtained from the correspondingly substituted salicylic acid byacylating the free acid with an acid anhydride in the presence of astrong acid such as perchloric acid or sulfuric acid, and treating theresulting 2-acyloxy compound with, for example, thionyl chloride orphosphorous pentachloride to produce Z-acyloxy nuclearly substitutedbenzoyl chloride.

EXAMPLE 56 2-Acetoxy-3'-Chloro-4'-(p-Chlorophenoxy)-3,5Dibromobenzanilide A mixture of 31.3 g. (0.123 mole) of 4-amino-2,4'-dichlorobiphenylether and ml. of anhydrous toluene is refluxed withstirring and a solution of 43.7 g. of 2-acetoxy-3,5-dibromobenzoylchloride in ml. of toluene is added dropwise.After 6 hours of reflux the reaction mixture is allowed to cool to roomtemperature and then concentrated in vacuo to a brown oil. This is takenup in chloroform and washed with dilute hydrochloric acid and dilutesodium bicarbonate solution and again concentrated in vacuo to a brownoil. This is taken up in chloroform and washed with dilutehydrochloricacid and dilute sodium bicarbonate solution and againconcentrated in vacuo to a brown oil. This is crystallized from abenzene-petroleum benzene mixture and then recrystallized twice fromisopropanol, giving 33.5 g. of2-acetoxy-3'-chloro-4'-(pchlorophenoxy)-3,S-dibromobenzanilide, m.p. l47148C.

When in the above process 2,6-diacetoxy-3,5- dibromobenzoyl chloride isused in place of 2-acetoxy- S-dibromobenzoyl chloride, there is obtained2,6- diacetoxy-3 -chloro-4 '-(p-chlorophenoxy )-3 ,5-dibromobenzanilide, mp. 18 l-l 83C.

What is claimed is: l. A method for the treatment of liver fluke infec-.

tive amount of a compound having the formula:

X A X6 5 ii i Y c N Q 2 EXAMPLE 57 3 ,S-Dibromo 3'-Chloro-4'-(p-Bromo-m-Trifluoromethylphenoxy Salicylanilide To a refluxingsolution of 0.925 g. (0.00252 mole) of 4-amino-4 '-bromo-2-chloro-3-trifluoromethylbiphenyl ether in 5 ml. of toluene is added dropwise asolution of 0.899 g. (0.00252 mole) of 2-acetoxy-3,5- dibromobenzoylchloride in 5 ml. of toluene with vigor-' ous stirring. When addition iscomplete, refluxing is continued for a full 6 hours. The product isallowed to crystallize overnight and collected by filtration. The yieldis 0.800 g. of crude 2-acetoxy-3,5-dibromo-3'-chloro-4'-(p-bromo-m-trifluoromethylphenoxy)- benzanilide. This isimmediately suspended in 9 ml. of ethanol and boiled on a steam bath. Tothe boiling reaction mixture is added a solution of 0.57 g. of potassiumhydroxide in 3 ml. of water. Solution occures immediately. While stillwarm, it is acidified with concentrated hydrochloric acid. A brownprecipitate forms, which is collected by filtration and washed withwater. The crude precipitate is crystallized several times frombenzene-petroleum-benzene, giving brown crystals, m.p. l65168. Theproduct is recrystallized from aqueous ethanol to give crystals having am.p. of 168169C.

It should be understood that although this invention has been describedwith reference to particular embodiments thereof, changes andmodifications may be made which are within its intended scope, and itshould be limited only by the language of the appended claims.

or a pharmaceutically acceptable salt thereof, wherein A is hydrogen orloweralkanoyl containing 2-4 carbon atoms;

Y is hydrogen, halogen, cyano, nitro or loweralkyl containing 1-4carbons;

Y is hydrogen or trifluoromethyl Y is hydrogen, halogen, or nitro;

Y is hydrogen, halogen, hydroxy, loweralkoxy containing 1-4 carbons, orloweralkanoyloxy containing 2-4 carbons;

X .is hydrogen, hydroxy, halogen, nitro, trifluoromethyl, or loweralkoxycontaining l4 carbons;

X is hydrogen, halogen, trifluoromethyl, nitro,

amino or loweralkoxy containing l-4 carbons;

X is hydrogen or halogen;

X is hydrogen or halogen;

Q is oxygen or sulfur;

Z is hydrogen, halogen, or loweralkyl containing l-4 carbons;

Z is hydrogen, halogen, trifluoromethyl, loweralkyl containing 1-4carbons, or cyano;

Z is hydrogen, halogen, cyano, nitro, trifluoromethyl loweralkylcontaining l-4 carbons, or loweralkoxy containing 1-4 carbons;

Z is hydrogen, halogen, or trifluoromethyl; and

Z is hydrogen or halogen; provided that no more than three substituentsother than hydrogen are present on any one of the aromatic rings at anyone time.

2. A method for the treatment of liver fluke infections which comprisesorally or' parenterally administering to an animal infected with liverfluke, an effective amount of a compound having the formula:

x x Z 2 Z 3 6 or a pharmaceutically acceptable salt thereof, wherein 3.The method of claim 2 wherein the Y and Y of A is y g the compound beingadministered to the host is iodo.

Q is oxygen or sulfur;

Y and Y are halogen, and Y is hydrogen;

X X X and X are each hydrogen or halogen provided that at least two arehydrogen;

Z Z Z Z and Z are each hydrogen or halogen provided that at least twoare hydrogen.

4. The method of claim 2 wherein the compound being administered is3,5-diiodo-3'-chloro-4'-(pchlorophenoxy)-salicylanilide.

1. A METHOD FOR THE TREATMENT OF LIVER FLUKE INFECTIONS WHICH COMPRISESORALLY OR PARENTERALLY ADMINISTERING TO AN ANIMAL INFECTED WITH LIVERFLUKE, AN EFFECTIVE AMOUNT OF A COMPOUND HAVING THE FORMULA:
 2. A methodfor the treatment of liver fluke infections which comprises orally orparenterally administering to an animal infected with liver fluke, aneffective amount of a compound having the formula:
 3. The method ofclaim 2 wherein the Y3 and Y5 of the compound being administered to thehost is iodo.
 4. The method of claim 2 wherein the compound beingadministered is3,5-diiodo-3''-chloro-4''-(p-chlorophenoxy)-salicylanilide.